The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system
Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffold...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2017-05-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/10/5/605 |
| _version_ | 1828750109919150080 |
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| author | Marta Chaverra Lynn George Marc Mergy Hannah Waller Katharine Kujawa Connor Murnion Ezekiel Sharples Julian Thorne Nathaniel Podgajny Andrea Grindeland Yumi Ueki Steven Eiger Cassie Cusick A. Michael Babcock George A. Carlson Frances Lefcort |
| author_facet | Marta Chaverra Lynn George Marc Mergy Hannah Waller Katharine Kujawa Connor Murnion Ezekiel Sharples Julian Thorne Nathaniel Podgajny Andrea Grindeland Yumi Ueki Steven Eiger Cassie Cusick A. Michael Babcock George A. Carlson Frances Lefcort |
| author_sort | Marta Chaverra |
| collection | DOAJ |
| description | Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed. |
| first_indexed | 2024-12-10T20:33:11Z |
| format | Article |
| id | doaj.art-180ee8b9118346feb641451aca5047e5 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-10T20:33:11Z |
| publishDate | 2017-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-180ee8b9118346feb641451aca5047e52022-12-22T01:34:37ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112017-05-0110560561810.1242/dmm.028258028258The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous systemMarta Chaverra0Lynn George1Marc Mergy2Hannah Waller3Katharine Kujawa4Connor Murnion5Ezekiel Sharples6Julian Thorne7Nathaniel Podgajny8Andrea Grindeland9Yumi Ueki10Steven Eiger11Cassie Cusick12A. Michael Babcock13George A. Carlson14Frances Lefcort15 Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Psychology, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA McLaughlin Research Institute, Great Falls, MT 59405, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Department of Psychology, Montana State University, Bozeman, MT 59717, USA McLaughlin Research Institute, Great Falls, MT 59405, USA Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.http://dmm.biologists.org/content/10/5/605Familial dysautonomiaElongatorHereditary sensory and autonomic neuropathy |
| spellingShingle | Marta Chaverra Lynn George Marc Mergy Hannah Waller Katharine Kujawa Connor Murnion Ezekiel Sharples Julian Thorne Nathaniel Podgajny Andrea Grindeland Yumi Ueki Steven Eiger Cassie Cusick A. Michael Babcock George A. Carlson Frances Lefcort The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system Disease Models & Mechanisms Familial dysautonomia Elongator Hereditary sensory and autonomic neuropathy |
| title | The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system |
| title_full | The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system |
| title_fullStr | The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system |
| title_full_unstemmed | The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system |
| title_short | The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system |
| title_sort | familial dysautonomia disease gene ikbkap is required in the developing and adult mouse central nervous system |
| topic | Familial dysautonomia Elongator Hereditary sensory and autonomic neuropathy |
| url | http://dmm.biologists.org/content/10/5/605 |
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